Targeting HDAC3 Reveals Therapeutic Vulnerability in PTENDeficient Endometrial Cancer

Endometrial Cancer (EC) is the most prevalent gynecologic malignancy, and its incidence continues to rise globally. PTEN mutations occur frequently in EC and lead to aberrant activation of the PI3K/AKT pathway, driving uncontrolled cellular proliferation and survival. In murine models, uterine-specific deletion of Pten results in rapid EC development. Emerging evidence implicates Histone Deacetylases (HDACs) as key epigenetic regulators of tumor progression, yet the specific role of HDAC3 in EC remains poorly defined.

We generated uterine-specific Pten and Hdac3 double-knockout mice (Pgrcre/+Hdac3f/fPtenf/f; Hdac3d/dPtend/d) to investigate the functional and therapeutic relevance of HDAC3. Histopathologic analysis was performed to examine the effect of Hdac3 ablation on EC with Pten deficiency compared with Pten single-knockout mice (Pgrcre/+Ptenf/f; Ptend/d) at 1 and 2 months of age. To evaluate the effect of the HDAC3 inhibitor (RGFP966), 6-week-old Ptend/d (Stage Ⅰ EC) mice were treated with vehicle or RGFP966 (10 mg/kg) twice per week for 5 weeks via intraperitoneal injection.

Histopathological analysis revealed marked regression of EC in Hdac3d/dPtend/d mice compared to Ptend/d controls to investigate the functional and therapeutic relevance of HDAC3. Pharmacologic inhibition of HDAC3 using the selective inhibitor RGFP966 in Ptend/d mice significantly reduced tumor burden and metastatic dissemination compared to vehicle treatment. Mechanistically, HDAC3 inhibition suppressed tumor cell proliferation and enhanced apoptosis, concomitant with reduced phosphorylation of ERK1/2 and AKT levels.

While our findings demonstrate significant antitumor effects of HDAC3 inhibition in PTEN-deficient endometrial cancer, further studies are needed to define the downstream molecular pathways responsible for these effects.

Collectively, these findings establish HDAC3 as a critical epigenetic driver of endometrial tumorigenesis and support selective HDAC3 inhibition as a promising therapeutic strategy for PTEN-deficient EC.